Derivatives of 2-oxoalkyl-1-piperazin-2-one, preparation method thereof and therapeutic use of same

ABSTRACT

The present invention relates to derivatives of 4-{2-[phenyl-3,6-dihydropyridin-1-yl]-2-oxoalkyl}-1-piperazin-2-one and 4-{2-[phenyl-2,5-dihydropyrrol-1-yl]-2-oxoalkyl}-1-piperazin-2-one having general formula (I): 
     
       
         
         
             
             
         
       
     
     in which A, B, m, R3 and n are as defined herein. The invention also relates to the preparation thereof and to the therapeutic use thereof.

The present invention relates to4-{2-[phenyl-3,6-dihydropyridin-1-yl]-2-oxoalkyl}-1-piperazin-2-one and4-{2-[phenyl-2,5-dihydropyrrol-1-yl]-2-oxoalkyl}-1-piperazin-2-onederivatives, to the preparation thereof and to the therapeutic usethereof.

The compounds according to the present invention have an affinity forthe p75^(NTR) neurotrophin receptor.

Neurotrophins belong to a family of proteins of which the biologicaleffect is in particular cell survival and differentiation.

The p75^(NTR) receptor, the receptor for all neurotrophins, is atransmembrane glycoprotein of the tumour necrosis factor (TNF) receptorfamily (W. J. Friedman and L. A. Greene, Exp. Cell. Res., 1999, 253,131-142). The p75^(NTR) receptor is expressed in several cell types, andseveral biological functions have been attributed to said receptor: onthe one hand, modulation of the affinity of neurotrophins for tyrosinekinase (trk) receptors; on the other hand, in the absence of trk,induction of a signal for cell death by apoptosis. Moreover, theneurotrophin precursors, proneurotrophins, are capable of binding top75^(NTR) with a high affinity, and are considered to be powerfulp75^(NTR)-dependent inducers of apoptosis in neurons and certain celllines.

At the level of the central nervous system, many studies show thatapoptosis occurs in several pathological conditions, such as amyotrophiclateral sclerosis, multiple sclerosis, Alzheimer's disease, Parkinson'sdisease and Huntington's disease and prion diseases. P75^(NTR) is alsoknown to be overexpressed in various types of neurodegenerativediseases, such as Alzheimer's disease and amyotrophic lateral sclerosis(ALS) (Longo F. M. et al., Curr. Alzheimer Res. 2007;4: 503-506; LowryK. S. et al., Amyotroph. Lateral. Scler. Other. Motor. Neuron. Disord.2001; 2:127-34).

Results suggest that p75^(NTR) may play a predominant role in themechanisms resulting in post-ischaemic apoptotic neuron death (P. P.Roux et al., J. Neurosci., 1999, 19, 6887-6896).

Results (V. Della-Bianca et al., J. Biol. Chem., 2001, 276: 38929-33),(S. Rabizadeh et al., Proc. Natl. Acad. Sci. USA, 1994,91, 10703-10706)support the hypothesis that p75^(NTR) plays an important role in neurondeath induced by prion protein infections (transmissible spongiformencephalopathy) or by beta-amyloid protein (Alzheimer's disease).

The p75^(NTR) receptor is also associated with the Nogo receptor andinvolved in the signalling of the inhibitory effects of these myelinproteins on axon growth. As a result the p75^(NTR) receptor plays amajor role in the regulation of the neuronal plasticity and inneuron-glia interactions, and thus represents a therapeutic target ofchoice for promoting nerve regeneration.

Beyond the nervous system and neurodegenerative diseases, it has beensuggested that p75^(NTR) could play a role in cardiovascular diseases,such as atherosclerosis and myocardial ischaemia (M. L. Bochaton-Pialatet al., Am. J. Pathol., 1995,146, 1-6; H. Perlman, Circulation, 1997,95, 981-987). Recent studies show an increase in the expression ofp75^(NTR) and of neurotrophins, and a massive apoptosis inatherosclerosis lesions.

Several studies also suggest that p75^(NTR) is an inflammation mediator(Rihl M. et al., Ann. Rheum. Dis. 2005; 64(11):1542-9; Raychaudhuri S.P. et al., Prog. Brain. Res. 2004; 146: 433-7, Tokuoka S. et al., Br. J.Pharmacol. 2001, 134: 1580-1586).

P75^(NTR) also plays an essential role in tumour biology.

Many compounds are known to interact with the trkA/NGF/p75^(NTR) systemor to have an NGF-type (nerve grown factor) activity. Thus patentapplication WO 00/59893 describes substituted pyrimidine derivativeswhich have an NGF-type activity and/or which increase the activity ofNGF on PC12 cells.

Patent application WO 03/104225 describes compounds which exhibitaffinity for P75^(NTR) receptors. These compounds are highly metabolizedand exhibit high percentages of inhibition of the hERG gene (the humanEther-a-go-go Related Gene).

The hERG gene encodes the K_(v)11.1. protein of a potassium ion channel.This protein is known for its contribution to the electrical activity ofthe heart. When the ability of the channel to conduct the electriccurrent through the cell membrane is inhibited by the action ofmedicaments, it may result in a potentially fatal disorder called QTsyndrome. A certain number of medicaments have inhibited this protein,creating a concomitant risk of sudden death as an adverse side effect.This has made hERG inhibition a central question both in the regulationof medicaments and in the development thereof (Sanguinetti M C,Tristani-Firouzi M (March 2006). “hERG potassium channels and cardiacarrhythmia”. Nature 440 (7083): 463-9).

A subject of the present invention is novel compounds which exhibitaffinity for P75^(NTR) receptors and which do not have the drawbacks ofhigh metabolization and of strong hERG inhibition that the prior artcompounds have. It therefore provides an advantage for the developmentof new medicaments.

A subject of the present invention is the compounds corresponding to theformula (I):

in which:

-   m is 0 or 1;-   A is:

-   and B is a hydrogen atom    or-   A is a hydrogen atom and B is:

-   R1 and R2, which may be identical or different, are independently a    hydrogen or halogen atom, a C₁-C₄ alkyl, C₁-C₄ fluoroalkyl, C₁-C₂    perfluoroalkyl or C₁-C₄ alkoxy group or a trifluoromethoxy group;-   n is 1 or 2;-   R3 is a group of formula:

where R4 and R5, which may be identical or different, are located on anyavailable positions and are independently a hydrogen or halogen atom, ahydroxyl, a C₁-C₄ alkyl, C₁-C₄ fluoroalkyl, C₁-C₂ perfluoroalkyl orC₁-C₄ alkoxy group, a trifluoromethoxy group, a cyano group, or a COOH,COOalkyl, CONH₂, CONR6R7 or NHCOR group;

-   R, R6 and R7 are a C₁-C₆ alkyl.

The compounds of formula (I) may comprise one or more asymmetricalcarbon atoms. They may therefore exist in the form of enantiomers ordiastereoisomers. These enantiomers and diastereoisomers and alsomixtures thereof, including racemic mixtures, form part of theinvention.

The compounds of formula (I) may exist in the form of bases or ofaddition salts with acids. Such addition salts form part of theinvention.

These salts may be prepared with pharmaceutically acceptable acids, butthe salts of other acids that are useful, for example, for purifying orisolating the compounds of formula (I) also form part of the invention.

In the context of the present invention:

-   -   the term “a halogen atom” is intended to mean: a fluorine, a        chlorine, a bromine or an iodine;    -   the term “an alkyl group” is intended to mean: a linear or        branched, saturated aliphatic group. By way of examples, mention        may be made of a C₁-C₄ alkyl group which may represent a methyl,        ethyl, propyl, isopropyl, butyl, isobutyl or tert-butyl;    -   the term “a fluoroalkyl group” is intended to mean: an alkyl        group of which one or more hydrogen atoms have been substituted        with a fluorine atom;    -   the term “a perfluoroalkyl group” is intended to mean: an alkyl        group of which all the hydrogen atoms have been substituted with        a fluorine atom;    -   the term “an alkoxy group” is intended to mean: an —O-alkyl        group where the alkyl group is as defined above.

Among the compounds of formula (I) which are subjects of the invention,another group of compounds is constituted of those for which R4 and R5,which may be identical or different, are located on any availablepositions, and are independently CONH₂, CONR6R7 or NHCOR, R, R6 and R7being defined as above;

in the form of bases or of addition salts with acids.

Among the compounds of formula (I) which are subjects of the invention,another group of compounds is constituted of the compounds of formula(I) in which:

-   m is 1;-   A is:

and B is a hydrogen atom;

-   R1 and R2, which may be identical or different, are independently a    hydrogen or halogen atom, a C₁-C₄ alkyl, C₁-C₄ fluoroalkyl, C₁-C₂    perfluoroalkyl or C₁-C₄ alkoxy group or a trifluoromethoxy group;-   n is 1 or 2;-   R3 is a group of formula:

where R4 and R5, which may be identical or different, are located on anyavailable positions and are independently a hydrogen or halogen atom, ahydroxyl, a C₁-C₄ alkyl, C₁-C₄ fluoroalkyl, C₁-C₂ perfluoroalkyl orC₁-C₄ alkoxy group, a trifluoromethoxy group, a cyano group, or a COOHor COOalkyl group; in the form of bases or of addition salts with acids.

Among the compounds of formula (I) which are subjects of the invention,another group of compounds is constituted of those for which R1 is otherthan H, R2 being as defined above;

in the form of bases or of addition salts with acids.

Among the compounds of formula (I) which are subjects of the invention,another group of compounds is constituted of the compounds for which:

R1 is in position -2-, -3- or -4- of the phenyl and is a halogen atom ormore particularly a chlorine atom, or a CF₃ radical, and R2 is ahydrogen or a 3- or 4-halogen, more particularly a 3- or 4-Cl; or elseR1 is in position 2-, 3- or 4- and is a chlorine atom or a CF₃ radicaland R2 is a hydrogen atom; or else R1 is in position 3- of the phenyland is a CF₃ radical, and R₂ is in position 4- of the phenyl and is achlorine atom; or else R1 is in position 2- of the phenyl atom and is achlorine atom, and R2 is in position 3- of the phenyl and is a chlorineatom; and/or

R3 is a 2-pyridynyl or a 2-pyrimidinyl, each substituted with R4 and R5as defined above; and/or

n=1;

in the form of bases or of addition salts with acids.

Among the compounds of this latter group, mention may be made of thecompounds of formula (I) for which:

R1 is 3-CF₃;

R2 is 4-chloro;

R3 is a 2-pyridyl residue 5-substituted with a CF₃; and

n=1;

in the form of bases or of addition salts with acids.

Among the compounds of formula (I) which are subjects of the invention,mention may in particular be made of the following compounds:

-   -   Compound No. 1:        4-{2-[4-(4-chloro-3-trifluoromethylphenyl)-3,6-dihydro-2H-pyridin-1-yl]-2-oxoethyl}-1-(5-trifluoromethylpyridin-2-yl)piperazin-2-one;    -   Compound No. 2:        4-{2-[4-(4-chloro-3-trifluoromethylphenyl)-3,6-dihydro-2H-pyridin-1-yl]-2-oxoethyl}-1-(5-methylpyridin-2-yl)piperazin-2-one;    -   Compound No. 3:        4-{2-[4-(4-chlorophenyl)-3,6-dihydro-2H-pyridin-1-yl]-2-oxoethyl}-1-(5-trifluoromethylpyridin-2-yl)piperazin-2-one;    -   Compound No. 4:        4-{2-oxo-2-[4-(3-trifluoromethylphenyl)-3,6-dihydro-2H-pyridin-1-yl]ethyl}-1-pyridin-2-ylpiperazin-2-one;    -   Compound No. 5:        4-{2-[4-(4-chloro-3-trifluoromethylphenyl)-3,6-dihydro-2H-pyridin-1-yl]-2-oxoethyl}-1-pyridin-2-ylpiperazin-2-one;    -   Compound No. 6:        4-{2-[4-(4-chlorophenyl)-3,6-dihydro-2H-pyridin-1-yl]-2-oxoethyl}-1-pyridin-2-yl-piperazin-2-one;    -   Compound No. 7:        4-{2-[4-(2,3-dichlorophenyl)-3,6-dihydro-2H-pyridin-1-yl]-2-oxoethyl}-1-(5-trifluoromethylpyridin-2-yl)piperazin-2-one;    -   Compound No. 8:        4-{2-[4-(4-chlorophenyl)-3,6-dihydro-2H-pyridin-1-yl]-2-oxoethyl}-1-(6-chloropyridin-2-yl)piperazin-2-one;    -   Compound No. 9:        4-{2-[4-(3-chlorophenyl)-3,6-dihydro-2H-pyridin-1-yl]-2-oxoethyl}-1-(5-trifluoromethylpyridin-2-yl)piperazin-2-one;    -   Compound No. 10:        4-{2-[4-(4-trifluoromethylphenyl)-3,6-dihydro-2H-pyridin-1-yl]-2-oxoethyl}-1-(5-trifluoromethylpyridin-2-yl)piperazin-2-one;    -   Compound No. 11:        4-{2-[4-(3-trifluoromethylphenyl)-3,6-dihydro-2H-pyridin-1-yl]-2-oxoethyl}-1-(5-trifluoromethylpyridin-2-yl)piperazin-2-one;    -   Compound No. 12:        4-{2-[4-(4-chloro-3-trifluoromethylphenyl)-3,6-dihydro-2H-pyridin-1-yl]-2-oxoethyl}-1-pyridin-3-ylpiperazin-2-one;    -   Compound No. 13:        1-(6-chloropyridin-3-yl)-4-{2-[4-(4-chloro-3-trifluoromethylphenyl)-3,6-dihydro-2H-pyridin-1-yl]-2-oxoethyl}piperazin-2-one;    -   Compound No. 14:        4-{2-oxo-2-[5-(3-trifluoromethylphenyl)-3,6-dihydro-2H-pyridin-1-yl]ethyl}-1-(5-trifluoromethylpyridin-2-yl)piperazin-2-one;    -   Compound No. 15:        4-{2-oxo-2-[4-(3-trifluoromethoxylphenyl)-3,6-dihydro-2H-pyridin-1-yl]ethyl}-1-pyridin-2-ylpiperazin-2-one;    -   Compound No. 16:        4-{2-[4-(4-chloro-3-trifluoromethylphenyl)-2,5-dihydro-pyrrol-1-yl]-2-oxoethyl}-1-(5-trifluoromethylpyridin-2-yl)piperazin-2-one;    -   Compound No. 17:        4-{2-[4-(3,5-bistrifluoromethylphenyl)-3,6-dihydro-2H-pyridin-1-yl]-2-oxoethyl}-1-(5-trifluoromethylpyridin-2-yl)piperazin-2-one;    -   Compound No. 18:        4-{2-[4-(3-methylphenyl)-3,6-dihydro-2H-pyridin-1-yl]-2-oxoethyl}-1-(5-trifluoromethylpyridin-2-yl)piperazin-2-one;    -   Compound No. 19:        4-{2-[4-phenyl-3,6-dihydro-2H-pyridin-1-yl]-2-oxoethyl}-1-(5-trifluoromethylpyridin-2-yl)piperazin-2-one;    -   Compound No. 20:        4-{2-oxo-2-[5-(2,3-dichlorophenyl)-3,6-dihydro-2H-pyridin-1-yl]ethyl}-1-(5-trifluoromethylpyridin-2-yl)piperazin-2-one;    -   Compound No. 21:        4-{2-oxo-2-[5-(3-methoxyphenyl)-3,6-dihydro-2H-pyridin-1-yl]ethyl}-1-(5-trifluoromethylpyridin-2-yl)piperazin-2-one;

in the form of bases or of addition salts with acids.

In the subsequent text, the term “protective group Pg” is intended tomean a group makes it possible, on the one hand, to protect a reactivefunction such as a hydroxyl or an amine during a synthesis and, on theother hand, to regenerate the intact reactive function at the end ofsynthesis. Examples of protective groups and also of the methods ofprotection and of deprotection are given in “Protective Groups inOrganic Synthesis”, Green et al., 2nd Edition (John Wiley & Sons, Inc.,New York).

In accordance with the invention, the compounds of general formula (I)are prepared according to the process which follows.

The compounds of formula (I) in which A, B, m, n and R3 are as definedabove, can be prepared by reaction of a compound of formula (IV) asdefined above, with a compound of formula (V) as defined above accordingto methods known to those skilled in the art as described inWO03/104225. More particularly, the process for preparing the compoundsof general formula (I) comprises the reaction of a compound of formula(IV):

in which A, B, m and n are as defined in general formula (I) and Halrepresents a halogen atom, for example chlorine,

-   and of a compound of general formula (V):

in which R3 is as defined in general formula (I) in the presence of abase, in a solvent as described in WO 03/104225. Thus, by way of base,mention may be made of organic bases such as triethylamine,N,N-diisopropylamine, diisopropylethylamine (DPEA), orN-methylmorpholine or alkali metal carbonates or bicarbonates such aspotassium carbonate, sodium carbonate or sodium bicarbonate and in theabsence or in presence of an alkali metal iodide such as potassiumiodide or sodium iodide. The reaction is carried out favourably in asolvent such as acetonitrile, N,N-dimethylformamide (DMF),N-methylpyrrolidone (NMP), toluene or propan-2-ol, at a temperaturebetween ambient temperature and the reflux temperature of the solvent.The term “ambient temperature” is intended to mean a temperature between5 and 25° C. By way of example, the reaction may be carried out in thepresence of sodium bicarbonate, and sodium iodide in a solvent such asDMF. The reaction is preferably carried out in a microwave reactor.

In the products of general formula (I) thus obtained, R, R1, R2, R4, R5,R6, and R7 can be modified by treatments commonly used by those skilledin the art, such as, for example, by hydrolysis of an ester group togive a carboxylic group.

The addition salts with an acid of the compounds of general formula (I)may be obtained by addition of the appropriate acid to the compound offormula (I) in the free base form.

The compounds of formula (IV), in which R1 and R2 are as defined for thecompounds of formula (I), can be prepared by reaction of a compound offormula (II) with a compound of formula (III) according to methods knownto those skilled in the art for example in presence of a base in asolvent as described in WO03/104225.

More particularly, the compounds of formula (IV) can be obtained byreaction of a corresponding compound of formula (II):

in which A, B and m are defined as in general formula (I); optionally inthe form of an addition salt with an acid, and of a compound of formula(III):

in which n and Hal are as defined in formula (IV) and Hal′ is a halogenatom, which may be identical or different. Preferably, Hal′ is achlorine atom.

This reaction is generally carried out in the presence of a base, suchas triethylamine, N,N-diisopropylethylamine or N-methylmorpholine, in asolvent such as dichloromethane, chloroform, tetrahydrofuran or dioxaneor a mixture of these solvents and at a temperature of between 0° C. andambient temperature. The compounds of formulae (II) and (III) aregenerally commercially available or can be prepared according to methodsknown to those skilled in the art.

The compounds of the formula (V), in which R3 is as defined in formula(I), are prepared according to methods known to those skilled in theart. They can be prepared, for example, according to the process whichfollows:

More particularly, the compound of formula (V) can be prepared from acorresponding compound of formula (XI), in which R3 is as defined informula (I) and Pg is a protective group for the nitrogen atom, such asbenzyl. This reaction can be carried out by application or adaptation ofany method known to those skilled in the art; generally, this reactionis carried out in an acidic medium, in the presence of a catalyst, suchas Pd/C.

The compound of formula (XI) can be obtained from a compound of formula(VIII) in which R3 is as defined in formula (I) and Pg is a protectivegroup, in the presence of a compound of formula (VI). Generally, thisreaction is carried out at a temperature between ambient temperature andthe boiling point of the reaction mixture that may comprise water.

Alternatively, the compound of formula (XI) can be obtained from acompound of formula (IX) by reaction with alkaline hydrides in inertsolvents such as toluene, dimethylformamide or dimethyl sulphoxide, at atemperature of between ambient temperature and the boiling point of thereaction mixture.

The compound of formula (IX) can be obtained from a compound of formula(VIII) by reaction with ethyl bromoacetate or ethyl chloroacetate insolvents such as butanol or acetone, in the presence of a base such aspotassium carbonate, at a temperature of between ambient temperature andthe boiling point of the reaction mixture.

The compound of formula (VIII) can be obtained from a compound offormula (VII) in which R3 is as defined in formula (I) and X is ahalogen atom, such as chlorine, in the presence of a compound of formula(X) in which Pg is a protective group as defined in formula (VIII).Generally, this reaction is carried out at a temperature between ambienttemperature and the boiling point of the reaction mixture.

Optionally, the process according to the invention comprises thesubsequent step consisting in isolating the desired product obtained.

According to another of its aspects, a subject of the invention is alsocompounds of formula (IV)

in which A, B, m and n are defined as in general formula (I) and Hal isa halogen atom, for example chlorine; in the form of bases or ofaddition salts with acids.

These compounds are of use as intermediates for synthesizing thecompounds of formula (I).

The starting compounds and the reactants, in Schemes 1 and 2, when themethod for the preparation thereof is not described, are commerciallyavailable or described in the literature, or else can be preparedaccording to methods which are described therein or which are known tothose skilled in the art.

The following examples describe the preparation of certain compounds inaccordance with the invention. These compounds are not limiting andmerely illustrate the present invention. The numbers of the compoundsexemplified refer back to those given in the table hereinafter, whichillustrates the chemical structures and the physical properties of somecompounds according to the invention.

The HPLC has been carried out using a ThermoElectron LCQ Deca XP Maxsystem equipped with a mass spectrometry ion trap detector and a diodearray detector.

The conditions for analysis by liquid chromatography coupled to massspectrometry (LC/UV/MS) are the following:

-   -   chromatographic system A    -   Eluent A=H₂O+0.01% TFA    -   Eluent B=CH₃CN    -   Gradient of 98% of A to 95% of B in 10 minutes, then elution        with 95% of B for 5 minutes.    -   Flow rate 0.5 ml/minute; temperature 40° C.    -   Injection of 2 μL of solution at 0.1 mg/ml in a mixture of        CH₃CN:H₂O=9:1        -   chromatographic system B    -   Eluent A=H₂O+0.05% TFA    -   Eluent B=CH₃CN+0.035% TFA    -   Gradient of 98% of A to 95% of B in 12 minutes, then elution        with 95% of B for 3 minutes.    -   Flow rate 0.7 ml/minute; temperature 40° C.    -   Injection of 2 μL of solution at 0.1 mg/ml in a mixture of        CH₃CN:H₂O=9:1        -   chromatographic system C    -   Eluent A=ammonium acetate buffer 5 mM pH 6.5    -   Eluent B=CH₃CN    -   Gradient of 98% of A to 95% of B in 10 minutes, then elution        with 95% of B for 5 minutes.    -   Flow rate 0.5 ml/minute; temperature 40° C.    -   Injection of 2 μL of solution at 0.1 mg/ml in a mixture of        CH₃CN:H₂O=9:1

The products are detected by UV at 220 nm.

The columns used are C18 columns with a particle size between 2 and 4μm, preferably 3.5 μm.

For the mass spectrometry part:

-   -   Ionization mode: positive electrospray (API-ES polarity+)    -   Scanning from 120 to 1500 uma

The proton nuclear magnetic resonance (¹H NMR) spectra were recordedunder the following conditions:

a) at 500 MHz on a Bruker machine equipped with an Avance III console;

b) at 400 MHz on a Bruker machine equipped with an Avance I console.

The chemical shifts are recorded in ppm with respect to the TMSfrequency.

The abbreviations used to characterize the signals are the following:s=singlet, bs=broad singlet, m=multiplet, bm=broad multiplet, d=doublet,bd=broad doublet, t=triplet, q=quadruplet.

*=not integratable because of interference with a broad peak due towater.

**=not integratable because of interference with a peak due to the NMRsolvent.

2Xm=two partially superimposed multiplets.

Preparation 1

1-(5-Trifluoromethylpyridin-2-yl)piperazin-2-one hydrochloride

10 g of 2-chloro-5-(trifluoromethyl)pyridine (compound of formula (VII))and 40.5 ml of N-benzylethylenediamine (compound of formula (X)) areheated at 135° C. for 6 hours in a round-bottomed flask. The mixture ispoured into water and the resulting mixture is extracted with ethylacetate. The resulting product is dried and evaporated to dryness; thecrude product thus obtained is purified by flash chromatography. Theisolated product (compound of formula (VIII)), 14 g, is solubilized in200 ml of a 2N solution of HCl. 30 g of trimeric glyoxal dihydrate(compound VI), are added and the mixture is left stirring at ambienttemperature for 72 hours. It is extracted with ethyl acetate. Theresulting product is dried and evaporated to dryness; the crude productthus obtained is purified by flash chromatography. The isolated product(compound of formula (IX)), 10 g, is solubilized in 450 ml of ethanol,and then 15 ml of a solution of isopropanol saturated with HCl and 3 gof Pd/C at 10% are added. The mixture is left to react under a hydrogenstream for 4 hours at a temperature of 40° C. The resulting product isfiltered and evaporated to dryness and 3 g of the title compound areobtained (compound of formula (V)) Melting point 205-207° C.

Preparation 2

1-(5-Methylpyridin-2-yl)piperazin-2-one hydrochloride

4.7 g of 2-chloro-5-methylpyridine (compound of formula (VII)) and 27.5ml of N-benzylethylenediamine (compound of formula (X)) are heated at135° C. for 5 hours in a round-bottomed flask. The mixture is pouredinto water and the resulting mixture is extracted with ethyl acetate.The resulting product is dried and evaporated to dryness; the crudeproduct thus obtained is purified by flash chromatography. A product of3.6 g is isolated (compound of formula (VIII)).

1.5 g of this product are solubilized in 3 ml of butanol. 0.85 g ofpotassium carbonate and 1.05 g of ethyl bromoacetate are added and themixture is heated at reflux temperature for 3 hours. It is poured intowater and extracted with ethyl acetate. The resulting product is driedand evaporated to dryness; the crude product thus obtained (2 g) ispurified by flash chromatography. The isolated product (compound offormula (IX)), 1 g, is then solubilized in toluene and then thissolution is slowly added, under a stream of nitrogen, to a suspension of0.25 g of sodium hydride at 60% (NaH) in 25 ml of toluene. The mixtureis heated at the reflux temperature for 2 hours. It is poured into waterand the resulting mixture is extracted with ethyl acetate. The resultingproduct is dried and evaporated under vacuum.

0.6 g of crude product is obtained in the form of an oil (compound offormula (IX)) which is solubilized in 25 ml of ethanol, and then 1.5 mlof a solution of isopropanol saturated with HCl and 0.3 g of 10% Pd/Care added. The mixture is left to react under a hydrogen stream for 4hours at a temperature of 40° C. The resulting product is filtered andevaporated under vacuum, and 0.3 g of the compound of the title(compound of formula (V)) is obtained.

Preparation 3

2-Chloro-1-[4-[3-trifluoromethyl-4-chlorophenyl]-1-[3,6-dihydro-1(2H)pyridinyl]]-1-ethanone

4-[3-(Trifluoromethyl)-4-chlorophenyl]-3,6-dihydro-1(2H)-pyridinehydrochloride (compound of formula (II)) (3.94 g) and 3.8 ml oftriethylamine in 33.5 ml of dichloromethane are cooled to 0° C.2-Chloroacetyl chloride (compound of formula (III)) is added dropwiseand the mixture is left stirring for 1 h 30. Water is added and theresulting mixture is extracted with dichloromethane. The organic phaseis dried over Na₂SO₄, filtered and evaporated under vacuum.

4.2 g of the compound are obtained in the form of an amorphous solid(compound of formula (IV)).

EXAMPLE 1 Compound No. 1:4-{2-[4-(4-chloro-3-trifluoromethylphenyl)-3,6-dihydro-2H-pyridin-1-yl]-2-oxoethyl}-1-(5-trifluoromethylpyridin-2-yl)piperazin-2-oneand the hydrochloride thereof

A mixture of compound of preparation 3 (0.49 mg), compound ofpreparation 1 (0.4 mg), potassium carbonate (0.41 g), and sodium iodide(0.45 g) in 7 ml of dimethylformamide is heated in a microwave reactorat 180° C. for 30 minutes. The reaction mixture is poured into water andthe resulting mixture is extracted with ethyl acetate. The organic phaseis dried over Na₂SO₄, filtered and evaporated, to give 700 mg of crudeproduct in the form of an oil. The product is purified by silica gelcolumn chromatography, elution being carried out with a mixture ofcyclohexane/ethyl acetate=1/1. The hydrochloride is prepared by adding asolution of hydrochloric acid in isopropanol. 200 g of the titlecompound are obtained.

M+H⁺=m/z 547

δ (ppm, dmso-d6): 2.55 (bs, **); 2.63 (m, **); 3.43-3-54 (m, 2H); 3.65(m, *); 3.75 (m,1H); 3.96 (bs, 2H); 4.18 (m, 6H); 6.40 (bs, 1H); 7.72(d, J=8.4 Hz, 1H), 7.74-7.80 (m, 1H), 7.80-7.85 (m, 1H), 8.21 (d, J=9Hz, 1H); 8.26 (dd, J₁=9 Hz, J₂=2 Hz, 1H); 8.88 (s, 1H).

EXAMPLE 2 Compound No. 2:4-{2-[4-(4-chloro-3-trifluoromethylphenyl)-3,6-dihydro-2H-pyridin-1-yl]-2-oxoethyl}-1-(5-methylpyridin-2-yl)piperazin-2-oneand the hydrochloride thereof

The compound of the title is obtained by carrying out the procedure asdescribed in Example 1, but using the compound of preparation 2 in placeof the compound of preparation 1.

M+H⁺=m/z 493

(Machine a). δ (ppm, dmso-d6): 2.32 (s, 3H), 2.56 (m, 1H), 2.65 (m, 1H),3.10-3.60 (m, *), 3.64 (m, 1H), 3.77 (m, 1H), 3.98 (m, 2H), 4.05-4.51(m, 6H), 6.41 (m, 1H), 7.69 (dd, J=8.4 and 2.0 Hz, 1H), 7.73 (d, 8.5 Hz,1H), 7.75-7.81 (m, 2H), 7.83 (bd, J=9.3 Hz, 1H), 8.31 (bd, J=2 Hz, 1H).

The table which follows illustrates the chemical structures and thephysical properties of some examples of compounds according to theinvention. In this table:

-   -   in the “salt” column, “-” represents a compound in the form of a        free base, whereas “HCl” represents a compound in the        hydrochloride form.

TABLE

No. A B m R3 n Salt Mp LCMS  1

H 1

1 HCl 210- 211 MH+ 547 r.t. 7.6 Method A  2

H 1

1 HCl 236- 239 MH+ 493 r.t. 6.5 Method A  3

H 1

1 — 141- 143 MH+ 479 r.t. 7.9 Method C  4

H 1

1 — 104- 106 MH+ 445 r.t. 5.4 Method A  5

H 1

1 HCl 160- 163 —  6

H 1

1 — 112- 115 MH+ 411 r.t. 5.4 Method A  7

H 1

1 — 145- 146 MH+ 513 r.t. 6.9 Method A  8

H 1

1 HCl 180- 181 MH+ 445 r.t. 7.2 Method A  9

H 1

1 HCl 147- 151 MH+ 479 r.t. 7.3 Method A 10

H 1

1 — 150- 152 MH+ 513 r.t. 7.9 Method C 11

H 1

1 Oxalate 161- 163 MH+ 513 r.t. 6.8 Method A 12

H 1

1 — — M+ = 479 r.t. 5.7 Method A 13

H 1

1 fumarate — M+ = 513 r.t. 6.5 Method A 14 H

1

1 Oxalate 172- 173 M+ = 513 r.t. 6.9 Method B 15

H 1

1 Oxalate 165- 166 M+ = 529 r.t. 7.1 Method A 16

H 0

1 — 210- 211 M+ = 533 r.t. 7.0 Method A 17

H 1

1 Oxalate 160- 161 M+ = 581 r.t. 8.1 Method C 18

H 1

1 — 130- 131 M+ = 459 r.t. 7.2 Method C 19

H 1

1 — 140- 142 M+ = 445 r.t. 6.0 Method A 20 H

1

1 Oxalate 177- 178 M+ = 513 r.t. 6.6 Method A 21 H

1

1 Oxalate 194- 195 M+ = 475 r.t. 5.9 Method A

The compounds according to the invention were the subject of biochemicalstudies.

Cell Culture:

The SH-SY-5Y strain (human neuroblastoma) is cultured conventionally ina DMEM culture medium (Dulbecco's Modified Eagle's Medium) (Gibco BRL,France) containing FCS (5%) (foetal calf serum) (Boehringer Mannheim,Germany), sodium pyruvate (1 mM) and glutamine (4 mM) in culture flaskscoated with collagen (Becton Dickinson, France).

The SK-N-BE parent strain (human neuroblastoma) and the Bep 75 clone,stably expressing the whole form of the human p75^(NTR) receptor(SK-N-BE Bep 75) are cultured conventionally in a RPMI culture mediumcontaining FCS (5%), sodium pyruvate (1 mM) and glutamine (4 mM). Forthe SK-N-BE Bep 75 cells, hygromycin (200 μl/20 ml of medium) is addedas selection agent.

Study of the Binding of the ¹²⁵I NGF to the p75^(NTR) Receptor

The NGF binding study (nerve grown factor radiolabelled with iodine-125,Amersham—2000 Ci/mmol) is carried out on a cell suspension of theSK-N-BE Bep 75 strain in accordance with the method described by Weskamp(Neuron, 1991, 6, 649-663). The nonspecific binding is determined bymeasuring the total binding after one hour of pre-incubation with thecells at 37° C. in the presence of non-radiolabelled NGF (1 μM). Thespecific binding is calculated by the difference between the totalbinding measurement and the non-specific binding measurement. Thecompetition experiments are carried out using an iodinated NGF (¹²⁵INGF) concentration of 0.3 nM. The concentrations inhibiting 50% (IC₅₀)of the binding of ¹²⁵I NGF to the p75^(NTR) receptor, of the compoundsaccording to the invention are low and vary from 10⁻⁶ to 10⁻¹¹ M.

The compounds of formula (I) exhibit an activity in this test, with IC₅₀values which range from 10⁻⁶ to 10⁻¹¹ M.

For example, the compounds of examples Nos. 3 and 1 showed an IC₅₀ of0.1 nM and 5.2 nM.

Study of the Dimerization of the p75^(NTR) Receptor Independently of itsLigand

The p75^(NTR) receptor dimerization study is carried out on a cellsuspension of the SK-N-BE Bep 75 strain. The cells (2.5 10⁴ cells/well)are placed in wells (96-well plate) for 24 h, and then preincubated for1 h at 37° C. in the presence or absence of the compounds according tothe invention. Supernatant is then added, this supernatant being derivedfrom the culture of HEK293 human cells of renal origin expressing, after48 h of transfection, and secreting a soluble form of the p75^(NTR)receptor (extracellular part of the receptor) coupled to an alkalinephosphatase, at the final concentration of 10 nM. The quantification ofthe specific binding of the soluble p75^(NTR) receptor to the receptorpresent on SK-N-BE Bep 75 cells is determined by measuring the alkalinephosphatase enzymatic activity after incubation of the cells for 1 hourat 37° C. in the presence of the supernatant. After filtration andtransfer of the filters into 24-well plates, the alkaline phosphataseactivity is determined by adding CDP-Star chemiluminescent substrate(ready-to-use, Roche). The concentrations inhibiting 50% (IC₅₀) of thedimerization of the p75^(NTR) receptor, of the compounds according tothe invention, are low and vary from 10⁻⁶ to 10⁻¹¹ M.

For example, the compounds of Examples No. 1, 2 and 3 showedrespectively IC₅₀ values of 1.34 nM, 3.88 nM and 0.11 nM.

Measurement of Apoptosis

The cells (human neuroblastoma strains SH-SY-5Y and SK-N-BE Bep 75) areplaced in 35 mm diameter Petri dishes (Biocoat collagen I), (10⁵cells/well) in an appropriate culture medium containing 5% of FCS for 24h. The culture medium is then removed, the cells are rinsed with PBS(Dulbecco's phosphate buffered saline), and then either fresh mediumcontaining 5% FCS, or medium containing NGF (at the concentration of 10ng/ml), or β-amyloid peptide (Aβ1-40) (at the concentration of 10 μM),is added, this being in the presence or absence of the compoundsaccording to the invention. The degrees of apoptosis are measured 48hours after the treatments in the case of the SH-SY-5Y strain, and 24hours after the treatments in the case of the SK-N-BE Bep 75 strain, byquantification of the DNA fragment-associated cytoplasmic histones (celldeath detection ELISA, Boehringer Mannheim, Germany). The degrees ofapoptosis are expressed as amount of oligonucleosomes/10⁵ cells. Eachvalue corresponds to the mean of 9 experimental points distributed over3 independent experiments.

The compounds of formula (I) exhibit an inhibitory activity onNGF-induced apoptosis, with IC₅₀ values which range from 10⁻⁶ to 10⁻¹¹M. For example, the compound of Example No. 1 showed an IC₅₀ of 1.61 nMand the compound of Example No. 5 showed an IC₅₀ of 52 nM.

Thus, the binding of the compounds according to the invention to thep75^(NTR) receptor is reflected, on the one hand at the biochemicallevel, by inhibition of the dimerization of the receptor induced byneurotrophins, or independently of the ligand, and, on the other hand,at the cellular level, by inhibition of the proapoptotic effect mediatedby the p75^(NTR) receptor.

Thus, according to one of the subjects of the present invention, thecompounds of formula (I) exhibit a very advantageous inhibitory activityon p75^(NTR) receptor dimerization independently of its ligand.

The compounds according to the invention can therefore be used for thepreparation of medicaments, in particular of medicaments for use inpreventing or treating any pathological condition where the p75^(NTR)receptor is involved.

Thus, according to another of its aspects, a subject of the invention ismedicaments which comprise a compound of formula (I), or an additionsalt of the latter with a pharmaceutically acceptable acid.

According to another of its aspects, a subject of the invention is acompound of formula (I), or an addition salt of the latter with apharmaceutically acceptable acid for the prevention or treatment of thepathological conditions indicated below.

Thus, the compounds according to the invention can be used, in humans orin animals, in the treatment or prevention of variousp75^(NTR)-dependent conditions, such as central and peripheralneurodegenerative diseases, for instance senile dementia, epilepsy,Alzheimer's disease, Parkinson's disease, Huntington's chorea, Down'ssyndrome, prion diseases, amnesia, schizophrenia, depression, bipolardisorder; amyotrophic lateral sclerosis, multiple sclerosis;cardiovascular conditions, for instance post-ischaemic cardiac damage,cardiomyopathies, myocardial infarction, heart failure, cardiacischaemia, cerebral infarction; peripheral neuropathies (of diabetic,traumatic or iatrogenic origin); damage to the optic nerve and to theretina (retinal pigment degeneration, glaucoma); retinal ischaemia;macular degeneration; spinal cord traumas and cranial traumas;atherosclerosis; stenoses; cicatrization disorders; alopecia.

The compounds according to the invention may also be used in thetreatment of cancers, for instance lung cancer, thyroid cancer,pancreatic cancer, prostate cancer, cancer of the small intestine and ofthe colon, or breast cancer, or in the treatment of tumours, ofmetastases and of leukaemias.

The compounds according to the invention may also be used in thetreatment of respiratory disorders, for instance pulmonary inflammation,allergy, asthma and chronic obstructive pulmonary disease.

The compounds according to the invention may also be used in thetreatment of cutaneous pain (in the skin, the subcutaneous tissues andthe associated organs), somatic pain, visceral pain (in the circulatory,respiratory, gastro-intestinal, or urogenital system), and neurologicalpain.

The compounds according to the invention may be used in the treatment ofchronic neuropathic and inflammatory pain and in the treatment ofautoimmune diseases, such as rheumatoid arthritis.

The compounds according to the invention may also be used in thetreatment of diseases such as ankylosing spondyl arthritis, psoriaticarthritis, or plaque psoriasis.

The compounds according to the invention may also be used in thetreatment of bone fractures, or in the treatment or the prevention ofbone diseases such as osteoporosis.

Thus, a subject of the present invention is a compound of formula (I)according to the invention for preventing or treating any pathologicalcondition where the p75^(NTR) receptor is involved or more particularlythe pathological conditions as indicated above.

According to another of its aspects, the present invention relates topharmaceutical compositions comprising, as active ingredients, acompound according to the invention. These pharmaceutical compositionscontain an effective dose of at least one compound according to theinvention, or a pharmaceutically acceptable salt of said compound, andalso at least one pharmaceutically acceptable excipient.

Said excipients are chosen, according to the pharmaceutical form and themethod of administration desired, from among the customary excipientswhich are known to those skilled in the art.

In the pharmaceutical compositions of the present invention for oral,sublingual, subcutaneous, intramuscular, intravenous, topical, local,intratracheal, intranasal, transdermic or rectal administration, theactive ingredient of formula (I) above, or salt thereof, may beadministered in unit administration form, as a mixture with conventionalpharmaceutical excipients, to animals and to human beings for theprevention or treatment of the disorders or diseases above.

The suitable unit administration forms comprise oral administrationforms such as tablets, hard or soft gel capsules, powders, granules andoral solutions or suspensions, sublingual, buccal, intratracheal,intraocular and intranasal administration forms, forms foradministration by inhalation, topical administration forms, parenteral,such as transdermal, administration forms, subcutaneous, intramuscularor intravenous administration forms, rectal administration forms andimplants. For topical application, the compounds according to theinvention may be used in creams, gels, ointments or lotions.

By way of example, a unit administration form of a compound according tothe invention in tablet form may comprise the following components:

Compound according to the invention 50.0 mg Mannitol 223.75 mg Sodiumcroscarmellose 6.0 mg Maize starch 15.0 mg Hydroxypropylmethylcellulose2.25 mg Magnesium stearate 3.0 mg

The dose of active ingredient administered per day may reach 0.01 to 100mg/kg, as one or more intakes, preferably 0.02 to 50 mg/kg. In general,the daily dose of the compound of the invention will be the lowesteffective dose of the compound capable of producing a therapeuticeffect.

There may be particular cases where higher or lower dosages areappropriate; such dosages do not depart from the context of theinvention. According to the customary practice, the dosage suitable foreach patient is determined by the physician according to the method ofadministration and the weight and response of said patient.

According to another of its aspects, the present invention also relatesto a method of treating the pathological conditions indicated above,which comprises the administration, to a patient, of an effective doseof a compound according to the invention, or a pharmaceuticallyacceptable salt thereof.

1. A method for the prevention or treatment of a condition selected fromthe group consisting of central and peripheral neurodegenerativediseases, senile dementia, epilepsy, Alzheimer's disease, Parkinson'sdisease, Huntington's chorea, Down's syndrome, prion diseases, amnesia,schizophrenia, depression, bipolar disorder, amyotrophic lateralsclerosis, multiple sclerosis, cardiovascular conditions, post-ischaemiccardiac damage, cardiomyopathies, myocardial infarction, heart failure,cardiac ischaemia, cerebral infarction, peripheral neuropathies, damageto the optic nerve and to the retina, retinal pigment degeneration,glaucoma, retinal ischaemia, macular degeneration, spinal cord traumas,cranial traumas, atherosclerosis, stenoses, cicatrization disorders,alopecia, cancers, tumours, metastases, leukaemias, respiratorydisorders, pulmonary inflammation, allergy, asthma, chronic obstructivepulmonary disease, cutaneous, somatic, visceral, and neurological pain,chronic neuropathic and inflammatory pain, autoimmune diseases,rheumatoid arthritis, ankylosing spondyl arthritis, psoriatic arthritis,plaque psoriasis, bone fractures, bone diseases and osteoporosis, themethod comprising administering to a patient in need thereof aneffective dose of a compound of formula (I):

in which: m is 0 or 1; A is:

and B is a hydrogen atom or A is a hydrogen atom and B is:

R1 and R2, which may be identical or different, are independently ahydrogen or halogen atom, a C₁-C₄ alkyl, C₁-C₄ fluoroalkyl, C₁-C₂perfluoroalkyl or C₁-C₄ alkoxy group or a trifluoromethoxy group; n is 1or 2; R3 is a group of formula:

where R4 and R5, which may be identical or different, are located on anyavailable positions, and are independently a hydrogen or halogen atom, ahydroxyl, a C₁-C₄ alkyl, C₁-C₄ fluoroalkyl, C₁-C₂ perfluoroalkyl, C₁-C₄alkoxy group, a trifluoromethoxy group, a cyano group, a COOH, COOalkyl,CONH₂, CONR6R7 or NHCOR group; and R, R6 and R7 are a C₁-C₆ alkyl; inthe form of a base or of an acid addition salt.
 2. The method accordingto claim 1, wherein for the compound of formula (I), R4 and R5, whichmay be identical or different, are located on any available positions,and are independently CONH₂, CONR6R7 or NHCOR; in the form of a base orof an acid addition salt.
 3. The method according to claim 1, whereinfor the compound of formula (I): m is 1; A is:

and B is a hydrogen atom; R1 and R2, which may be identical ordifferent, are independently a hydrogen or halogen atom, a C₁-C₄ alkyl,C₁-C₄ fluoroalkyl, C₁-C₂ perfluoroalkyl or C₁-C₄ alkoxy group or atrifluoromethoxy group; n is 1 or 2; R3 is a group of formula:

where R4 and R5, which may be identical or different, are located on anyavailable positions and are independently a hydrogen or halogen atom, ahydroxyl, a C₁-C₄ alkyl, C₁-C₄ fluoroalkyl, C₁-C₂ perfluoroalkyl orC₁-C₄ alkoxy group, a trifluoromethoxy group, a cyano group, or a COOHor COOalkyl group; in the form of a base or of an acid addition salt. 4.The method according to claim 1, wherein for the compound of formula(I), R1 is other than H; in the form of a base or of an acid additionsalt.
 5. The method according to claim 1, wherein for the compound offormula (I), R1 is in position -2-, -3- or -4- and is a chlorine atom ora CF₃ radical, and R2 is a hydrogen or a 3- or 4-Cl; in the form of abase or of an acid addition salt.
 6. The method according to claim 1,wherein for the compound of formula (I), R3 is a 2-pyridynyl or a2-pyrimidinyl, each substituted with R4 and R5 as defined in claim 1; inthe form of a base or of an acid addition salt.
 7. The method accordingto claim 1, wherein for the compound of formula (I), n=1; in the form ofa base or of an acid addition salt.
 8. The method according to claim 1,wherein for the compound of formula (I), R1 is 3-CF₃; R2 is 4-chloro; R3is a 2-pyridyl residue 5-substituted with a CF₃; and n=1; in the form ofa base or of an acid addition salt.
 9. The method according to claim 1,wherein the compound is selected from the group consisting of:4-{2-[4-(4-chloro-3-trifluoromethylphenyl)-3,6-dihydro-2H-pyridin-1-yl]-2-oxoethyl}-1-(5-trifluoromethylpyridin-2-yl)piperazin-2-one;4-{2-[4-(4-chloro-3-trifluoromethylphenyl)-3,6-dihydro-2H-pyridin-1-yl]-2-oxoethyl}-1-(5-methylpyridin-2-yl)piperazin-2-one;4-{2-[4-(4-chlorophenyl)-3,6-dihydro-2H-pyridin-1-yl]-2-oxoethyl}-1-(5-trifluoromethylpyridin-2-yl)piperazin-2-one;4-{2-oxo-2-[4-(3-trifluoromethylphenyl)-3,6-dihydro-2H-pyridin-1-yl]ethyl}-1-pyridin-2-ylpiperazin-2-one;4-{2-[4-(4-chloro-3-trifluoromethylphenyl)-3,6-dihydro-2H-pyridin-1-yl]-2-oxoethyl}-1-pyridin-2-ylpiperazin-2-one;4-{2-[4-(4-chlorophenyl)-3,6-dihydro-2H-pyridin-1-yl]-2-oxoethyl}-1-pyridin-2-yl-piperazin-2-one;4-{2-[4-(2,3-dichlorophenyl)-3,6-dihydro-2H-pyridin-1-yl]-2-oxoethyl}-1-(5-trifluoromethylpyridin-2-yl)piperazin-2-one;4-{2-[4-(4-chlorophenyl)-3,6-dihydro-2H-pyridin-1-yl]-2-oxoethyl}-1-(6-chloropyridin-2-yl)piperazin-2-one;4-{2-[4-(3-chlorophenyl)-3,6-dihydro-2H-pyridin-1-yl]-2-oxoethyl}-1-(5-trifluoromethylpyridin-2-yl)piperazin-2-one;4-{2-[4-(4-trifluoromethylphenyl)-3,6-dihydro-2H-pyridin-1-yl]-2-oxoethyl}-1-(5-trifluoromethylpyridin-2-yl)piperazin-2-one;4-{2-[4-(3-trifluoromethylphenyl)-3,6-dihydro-2H-pyridin-1-yl]-2-oxoethyl}-1-(5-trifluoromethylpyridin-2-yl)piperazin-2-one;4-{2-[4-(4-chloro-3-trifluoromethylphenyl)-3,6-dihydro-2H-pyridin-1-yl]-2-oxoethyl}-1-pyridin-3-yl-piperazin-2-one;1-(6-chloropyridin-3-yl)-4-{2-[4-(4-chloro-3-trifluoromethylphenyl)-3,6-dihydro-2H-pyridin-1-yl]-2-oxoethyl}piperazin-2-one;4-{2-oxo-2-[5-(3-trifluoromethylphenyl)-3,6-dihydro-2H-pyridin-1-yl]ethyl}-1-(5-trifluoromethylpyridin-2-yl)piperazin-2-one;4-{2-oxo-2-[4-(3-trifluoromethoxylphenyl)-3,6-dihydro-2H-pyridin-1-yl]ethyl}-1-pyridin-2-ylpiperazin-2-one;4-{2-[4-(4-chloro-3-trifluoromethylphenyl)-2,5-dihydropyrrol-1-yl]-2-oxoethyl}-1-(5-trifluoromethylpyridin-2-yl)piperazin-2-one;4-{2-[4-(3,5-bistrifluoromethylphenyl)-3,6-dihydro-2H-pyridin-1-yl]-2-oxoethyl}-1-(5-trifluoromethylpyridin-2-yl)piperazin-2-one;4-{2-[4-(3-methylphenyl)-3,6-dihydro-2H-pyridin-1-yl]-2-oxoethyl)-1-(5-trifluoromethylpyridin-2-yl)piperazin-2-one;4-{2-[4-phenyl-3,6-dihydro-2H-pyridin-1-yl]-2-oxoethyl}-1-(5-trifluoromethylpyridin-2-yl)piperazin-2-one;4-{2-oxo-2-[5-(2,3-dichlorophenyl)-3,6-dihydro-2H-pyridin-1-yl]ethyl}-1-(5-trifluoromethylpyridin-2-yl)piperazin-2-one;and4-{2-oxo-2-[5-(3-methoxyphenyl)-3,6-dihydro-2H-pyridin-1-yl]ethyl}-1-(5-trifluoromethylpyridin-2-yl)piperazin-2-one;in the form of a base or of an acid addition salt.
 10. A method forinhibiting p75^(NTR) receptor dimerization independently of its ligand,the method comprising administering to a patient in need thereof aneffective dose of a compound of formula (I):

in which: m is 0 or 1; A is:

and B is a hydrogen atom or A is a hydrogen atom and B is:

R1 and R2, which may be identical or different, are independently ahydrogen or halogen atom, a C₁-C₄ alkyl, C₁-C₄ fluoroalkyl, C₁-C₂perfluoroalkyl or C₁-C₄ alkoxy group or a trifluoromethoxy group; n is 1or 2; R3 is a group of formula:

where R4 and R5, which may be identical or different, are located on anyavailable positions, and are independently a hydrogen or halogen atom, ahydroxyl, a C₁-C₄ alkyl, C₁-C₄ fluoroalkyl, C₁-C₂ perfluoroalkyl, C₁-C₄alkoxy group, a trifluoromethoxy group, a cyano group, a COOH, COOalkyl,CONH₂, CONR6R7 or NHCOR group; and R, R6 and R7 are a C₁-C₆ alkyl; inthe form of a base or of an acid addition salt.
 11. The method accordingto claim 10, wherein for the compound of formula (I), R4 and R5, whichmay be identical or different, are located on any available positions,and are independently CONH₂, CONR6R7 or NHCOR; in the form of a base orof an acid addition salt.
 12. The method according to claim 10, whereinfor the compound of formula (I): m is 1; A is:

and B is a hydrogen atom; R1 and R2, which may be identical ordifferent, are independently a hydrogen or halogen atom, a C₁-C₄ alkyl,C₁-C₄ fluoroalkyl, C₁-C₂ perfluoroalkyl or C₁-C₄ alkoxy group or atrifluoromethoxy group; n is 1 or 2; R3 is a group of formula:

where R4 and R5, which may be identical or different, are located on anyavailable positions and are independently a hydrogen or halogen atom, ahydroxyl, a C₁-C₄ alkyl, C₁-C₄ fluoroalkyl, C₁-C₂ perfluoroalkyl orC₁-C₄ alkoxy group, a trifluoromethoxy group, a cyano group, or a COOHor COOalkyl group; in the form of a base or of an acid addition salt.13. The method according to claim 10, wherein for the compound offormula (I), R1 is other than H; in the form of a base or of an acidaddition salt.
 14. The method according to claim 10, wherein for thecompound of formula (I), R1 is in position -2-, -3- or -4- and is achlorine atom or a CF₃ radical, and R2 is a hydrogen or a 3- or 4-Cl; inthe form of a base or of an acid addition salt.
 15. The method accordingto claim 10, wherein for the compound of formula (I), R3 is a2-pyridynyl or a 2-pyrimidinyl, each substituted with R4 and R5 asdefined in claim 10; in the form of a base or of an acid addition salt.16. The method according to claim 10, wherein for the compound offormula (I), n=1; in the form of a base or of an acid addition salt. 17.The method according to claim 10, wherein for the compound of formula(I), R1 is 3-CF₃; R2 is 4-chloro; R3 is a 2-pyridyl residue5-substituted with a CF₃; and n=1; in the form of a base or of an acidaddition salt.
 18. The method according to claim 10, wherein thecompound is selected from the group consisting of:4-{2-[4-(4-chloro-3-trifluoromethylphenyl)-3,6-dihydro-2H-pyridin-1-yl]-2-oxoethyl}-1-(5-trifluoromethylpyridin-2-yl)piperazin-2-one;4-{2-[4-(4-chloro-3-trifluoromethylphenyl)-3,6-dihydro-2H-pyridin-1-yl]-2-oxoethyl}-1-(5-methylpyridin-2-yl)piperazin-2-one;4-{2-[4-(4-chlorophenyl)-3,6-dihydro-2H-pyridin-1-yl]-2-oxoethyl}-1-(5-trifluoromethylpyridin-2-yl)piperazin-2-one;4-{2-oxo-2-[4-(3-trifluoromethylphenyl)-3,6-dihydro-2H-pyridin-1-yl]ethyl}-1-pyridin-2-ylpiperazin-2-one;4-{2-[4-(4-chloro-3-trifluoromethylphenyl)-3,6-dihydro-2H-pyridin-1-yl]-2-oxoethyl}-1-pyridin-2-ylpiperazin-2-one;4-{2-[4-(4-chlorophenyl)-3,6-dihydro-2H-pyridin-1-yl]-2-oxoethyl}-1-pyridin-2-yl-piperazin-2-one;4-{2-[4-(2,3-dichlorophenyl)-3,6-dihydro-2H-pyridin-1-yl]-2-oxoethyl}-1-(5-trifluoromethylpyridin-2-yl)piperazin-2-one;4-{2-[4-(4-chlorophenyl)-3,6-dihydro-2H-pyridin-1-yl]-2-oxoethyl}-1-(6-chloropyridin-2-yl)piperazin-2-one;4-{2-[4-(3-chlorophenyl)-3,6-dihydro-2H-pyridin-1-yl]-2-oxoethyl}-1-(5-trifluoromethylpyridin-2-yl)piperazin-2-one;4-{2-[4-(4-trifluoromethylphenyl)-3,6-dihydro-2H-pyridin-1-yl]-2-oxoethyl}-1-(5-trifluoromethylpyridin-2-yl)piperazin-2-one;4-{2-[4-(3-trifluoromethylphenyl)-3,6-dihydro-2H-pyridin-1-yl]-2-oxoethyl}-1-(5-trifluoromethylpyridin-2-yl)piperazin-2-one;4-{2-[4-(4-chloro-3-trifluoromethylphenyl)-3,6-dihydro-2H-pyridin-1-yl]-2-oxoethyl}-1-pyridin-3-yl-piperazin-2-one;1-(6-chloropyridin-3-yl)-4-{2-[4-(4-chloro-3-trifluoromethylphenyl)-3,6-dihydro-2H-pyridin-1-yl]-2-oxoethyl}piperazin-2-one;4-{2-oxo-2-[5-(3-trifluoromethylphenyl)-3,6-dihydro-2H-pyridin-1-yl]ethyl}-1-(5-trifluoromethylpyridin-2-yl)piperazin-2-one;4-{2-oxo-2-[4-(3-trifluoromethoxylphenyl)-3,6-dihydro-2H-pyridin-1-yl]ethyl}-1-pyridin-2-ylpiperazin-2-one;4-{2-[4-(4-chloro-3-trifluoromethylphenyl)-2,5-dihydropyrrol-1-yl]-2-oxoethyl}-1-(5-trifluoromethylpyridin-2-yl)piperazin-2-one;4-{2-[4-(3,5-bistrifluoromethylphenyl)-3,6-dihydro-2H-pyridin-1-yl]-2-oxoethyl}-1-(5-trifluoromethylpyridin-2-yl)piperazin-2-one;4-{2-[4-(3-methylphenyl)-3,6-dihydro-2H-pyridin-1-yl]-2-oxoethyl}-1-(5-trifluoromethylpyridin-2-yl)piperazin-2-one;4-{2-[4-phenyl-3,6-dihydro-2H-pyridin-1-yl]-2-oxoethyl}-1-(5-trifluoromethylpyridin-2-yl)piperazin-2-one;4-{2-oxo-2-[5-(2,3-dichlorophenyl)-3,6-dihydro-2H-pyridin-1-yl]ethyl}-1-(5-trifluoromethylpyridin-2-yl)piperazin-2-one;and4-{2-oxo-2-[5-(3-methoxyphenyl)-3,6-dihydro-2H-pyridin-1-yl]ethyl}-1-(5-trifluoromethylpyridin-2-yl)piperazin-2-one;in the form of a base or of an acid addition salt.
 19. A compound offormula (IV)

in which A, B, m and n are as defined in claim 1 and Hal is a halogenatom; with the exception of2-chloro-1-[4-(2-methoxyphenyl)-3,6-dihydro-2H-pyridin-1-yl]-ethanoneand 2-chloro-1-[4-(4-bromophenyl)-3,6-dihydro-2H-pyridin-1-yl]ethanone;in the form of a base or of an acid addition salt.